Leqvio (inclisiran): what was done before first-in-human, and what came after?

Precedia/Oligonucleotides/Leqvio/Tox package

Leqvio: what was done before first-in-human, and what came after?

inclisiran · PCSK9 (siRNA)

Before first-in-human

First-in-human: where

Not stated in public reviews

Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.

Repeat-dose tox before first-in-human

Not stated in public reviews

Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.

First-in-human starting dose

Not stated in public reviews

Why it's blank

The public FDA and EMA reviews of Leqvio don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.

How it's usually set for oligonucleotides outside oncology

Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.

“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

This product's starting point

NOAEL / key findings: NOAEL = highest doses (250 mg/kg rat, 300 mg/kg monkey Q4W); non-adverse liver, kidney, injection site, lymph node accumulation findings (FDA pharmacology/toxicology review, p. 39)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

40-week cynomolgus monkey (SC, every 28 days) with 13-week recovery

“A 40-Week Repeat Subcutaneous Injection Toxicity and Toxicokinetic Study in the Cynomolgus Monkey Followed by a 13-Week Recovery Period (study no.: 5001352) Doses: 0, 30, 100, and 300 mg/kg/every 28 days by SC injection”

✓ VerifiedFDA pharmacology/toxicology review, p. 34Source ↗

Pivotal GLP studies

Rat 29-week and monkey 40-week SC Q4W (13-week recovery); plus 4- and 15-week studies and 13-week monkey statin combination

“Toxicological characterization of inclisiran was performed in studies of 29 weeks in rats and 40 weeks in NHPs at doses up to 8 times (≤ 250 mg/kg Q4W) and 19 times (300 mg/kg Q4W) the MRHD (based on BSA), respectively.”

✓ VerifiedFDA pharmacology/toxicology review, p. 5Source ↗

DART package

Species: DART

Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)

“Embryo-fetal assessments in rats and rabbits and a pre and postnatal development study in rats did not demonstrate evidence of reproductive or developmental risk at any dose tested, representing up to 5 and 10 times clinical MRHD (BSA), respectively (≤ 150mg/kg/day in both species). Inclisiran produced no adverse impact on fertility or early embryonic development in rats at up to 8 times the MRHD (BSA) (≤ 250 mg/kg/day).”